Identification of metabolites of valproic acid in serum of humans, dog, rat, and mouse.

In kinetic studies of VPA in humans, dogs, rats, and mice, as well as in clinical routine analysis of serum concentrations of VPA in epileptic patients, 2--4 peaks (depending on the species examined) were regularly found in the gas chromatograms in addition to VPA. Comparison with control serum indicated that these peaks resulted from metabolism of VPA. By GC--MS, two of these metabolites could be identified as 5-hydroxy-2-propyl-pentanoic acid (5-OH-VPA) and 4-hydroxy-2-propyl-pentanoic acid (4-OH-VPA), using synthesized reference substances. Both metabolites results from omega (omega1, omega2) oxidation of VPA, 5-OH-VPA only occurring in serum of mice, and 4-OH-VPA in serum of mice and humans. With the aid of low- and high-resolution mass spectra, likely structures of the two remaining metabolites, both of which were found in serum of all the species examined, were proposed. One of these, 3-hydroxy-2-propyl-pentanoic acid (3-OH-VPA) confirms the involvement of beta-oxidation in the metabolism of VPA. The fourth metabolite, whose identity is uncertain, indicates a substance not described previously as a metabolite of VPA.